Most asthma exacerbations in children and young adults result from rhinovirus (RV) infections. As the most important cause of asthma-related morbidity it is essential that clinical investigations be performed in humans to define the underlying mechanisms. We hypothesize that the immune responses generated in the nose of asthmatics underlie subsequent systemic modulation of the immune system, and that - in susceptible individuals (those with pre-existing asthma) - this modified nasal milieu is responsible for the asthma exacerbation. Specifically, we propose that this modification produces a distinct pattern of immune responsiveness to RV in the upper airway of asthmatics, which triggers the development of a Th2 cytokine signature state that drives the adverse outcome of RV infection in the lower airway of asthmatics. In addition, we propose that the intensity of this Th2-inducing nasal airway milieu is further exaggerated in these allergic asthmatics, by a concomitant defect in the development and expression of effective anti-RV immune responses, leading to greater susceptibility to RV. Determining the etiology of rhinovirus-induced asthma exacerbations will identify specific targets to prevent and treat these episodes. Specific Aim 1 will address the hypothesis that epigenetic changes develop in nasal epithelial cells (EC) during the evolution of allergic airway disease as a result of which nasal EC are programmed to produce cytokines central to orchestrating an allergic inflammatory immune response. We will primarily determine whether nasal epithelium from allergic asthmatics, when infected with RV, is programmed to secrete cytokines that promote a Th2 cytokine signature (IL-25, IL- 33, and TSLP). Specific Aim 2 will interrogate the complementary hypothesis that increased susceptibility to RV and extent of nasal infections in asthmatics amplifies the consequences of this Th2-inducing bias. Specifically we propose that over time nasal epithelium in asthmatics is epigenetically re-programmed, resulting in the greater susceptibility of EC to RV infection. Initially we will analyze nasal EC ex vivo to test the hypothesis that EC from asthmatics will be more susceptible to RV infection as manifested by a greater magnitude of RV replication, a more rapid tempo of infection and overall greater death of RV-infected cells. We will then corroborate this in vitro analysis with in vivo studies by infecting asthmatics and controls with RV, monitoring viral load over time as a measure of the pace of infection. Most importantly, we will perform nasal biopsies at the peak of infection to determine the extent of viral infection and whether this represents cytopathic (necrotic) or apoptotic cell death. And, finally, Specific Aim 3 will address the molecular and cellular basis for the defect in anti-viral immunity in asthma. We will establish primary cultures of EC from control and asthmatic individuals prior to RV infection and examine them for baseline- and RV infection- induced expression of cytokines central to anti-viral immunity (IFNs-?, -, and ? and IL-15). We expect that anti-viral mediator expression will correlate inversely with the susceptibility, tempo, and severity of RV infection.